Liver X-receptors (LXRs) are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. Most of the cholesterol in plasma is transported on three major lipoprotein classes; VLDL cholesterol (VLDL-C), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). Total cholesterol is the sum of all three lipoproteins. Both VLDL-C and LDL-C are associated with atherogenic processes while HDL-C is believed to facilitate cholesterol removal from tissues (e.g. atherosclerotic plaques) and thus have a protective effect on coronary heart disease.
LXR represents a novel intervention point to regulate the reverse cholesterol transport (RCT) pathway, i.e., the removal of cholesterol from peripheral tissues/cells and subsequent uptake via the liver for disposal. Removal of cellular cholesterol requires active transport of free cholesterol across the plasma membrane and onto HDL particles. This transfer of cholesterol from inside the cell and onto HDL in the plasma is mediated by ATP binding cassette 1 (ABCA1) transporter protein. The observation that LXR is a key transcriptional activator of ABCA1 in the macrophage, suggests that induction of LXR will lead to an increase in cholesterol efflux from the macrophage. In addition, it is known that LXR regulates the induction of other genes involved in RCT such as apoE and cholesterol ester transport protein (CETP), suggesting that activating the LXR pathway should also lead to increased uptake of cholesterol by the liver. Thus, activation of LXR by a small molecule ligand will lead to an up-regulation of ABCA1 and induction of the reverse cholesterol transport pathway thereby increasing cholesterol efflux to HDL-C and reducing the cholesterol content of atherosclerotic plaques.
In general, the present invention is directed to selective LXR modulators, small molecule compounds corresponding to Formula I and the isomers, tautomers, salts and prodrugs thereof: 
wherein:
the X ring and the M ring are independently aromatic rings;
M1, M2, M3, M4, and M5 are independently a bond, carbon, nitrogen, oxygen or sulfur, provided, however, no more than one of M1, M2, M3, M4, and M5 is a bond;
M11, M22, M33, M44, and M55 are independently an electron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, hydrocarbyloxy, substituted hydrocarbyloxy, mercapto, halo, heterocyclo, cyano, nitro, amino, acylamino, acylthio, or acyloxy, or any adjacent two of M11, M22, M33, M44, and M55 form a fused ring with the atoms of the M ring to which they are bonded; provided, however, M11, M22, M33, M44, and M55 is not present when M1, M2, M3, M4, or M5, respectively, is a bond;
p and q are independently 0, 1, or 2;
X1, X2, X3, and X4 are independently a bond, carbon, nitrogen, oxygen or sulfur, provided, however, no more than one of X1, X2, X3, and X4 is a bond;
X11, X22, X33, and X44, are independently an electron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, hydrocarbyloxy, substituted hydrocarbyloxy, mercapto, halo, heterocyclo, cyano, nitro, amino, acylamino, acylthio, acyloxy, or acyl; provided, however, X11, X22, X33, or X44 is not present when X1, X2, X3 or X4, respectively, is a bond;
X50 is carbon, sulfur or sulfoxide,
X51 is oxygen, sulfur, or NX52,
X52 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
X53 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or amino.
The present invention is further directed to a process for the treatment or prevention of a condition in a mammal which is modulated by LXR. The process comprises administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I or an isomer, tautomer, salt or prodrug thereof.
Other aspects of the invention will be in part apparent and in part pointed out hereinafter.